Non‐clinical single‐ and repeated‐dose toxicity studies of ET‐26 hydrochloride in rats

Zhang, Yinan; Zhang, Yujun; Deng, Chaoyi; Gong, Deying; Kang, Yi; Liu, Jin; Zhang, Wensheng

doi:10.1002/jat.3970

Cited by 4 publications

(3 citation statements)

References 13 publications

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“…The hemodynamic and adrenal stability together with superior myocardial performance following ET-26HCl administration [52] were demonstrated in rat models of hemorrhagic shock [53] and LPS-induced sepsis [54] resulting in overall better survival rates compared with etomidate parent compound. Recently completed studies in rats and beagle dogs have provided preclinical evidence about ET-26HCl safety profile [55 ▪ ,56,57], thus setting the stage for further testing in clinical trials.…”

Section: Etomidate Analogs: a Quest For Cardiovascular And Adrenal Sa...mentioning

confidence: 99%

Novel anesthetics in pediatric practice: is it time?

Useinovic¹,

Jevtović-Todorović²

2022

Current Opinion in Anaesthesiology

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Purpose of reviewSteadily mounting evidence of anesthesia-induced developmental neurotoxicity has been a challenge in pediatric anesthesiology. Considering that presently used anesthetics have, in different animal models, been shown to cause lasting behavioral impairments when administered at the peak of brain development, the nagging question, 'Is it time for the development of a new anesthetic' must be pondered. Recent findingsThe emerging 'soft analogs' of intravenous anesthetics aim to overcome the shortcomings of currently available clinical drugs. Remimazolam, a novel ester-analog of midazolam, is a well tolerated intravenous drug with beneficial pharmacological properties. Two novel etomidate analogs currently in development are causing less adrenocortical suppression while maintaining equally favorable hemodynamic stability and rapid metabolism. Quaternary lidocaine derivatives are explored as more potent and longer lasting alternatives to currently available local anesthetics. Xenon, a noble gas with anesthetic properties, is being considered as an anesthetic-sparing adjuvant in pediatric population. Finally, alphaxalone is being reevaluated in a new drug formulation because of its favorable pharmacological properties.

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Section: Etomidate Analogs: a Quest For Cardiovascular And Adrenal Sa...mentioning

confidence: 99%

Novel anesthetics in pediatric practice: is it time?

Useinovic¹,

Jevtović-Todorović²

2022

Current Opinion in Anaesthesiology

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“…Etomidate formulated in propylene glycol induces hemolysis after bolus injection in patients and healthy volunteers ( Doenicke et al, 1997 ; Doenicke et al, 1999 ). In the single dose and 14-days repeated-dose toxicity study of ET-26HCl in rats ( Zhang et al, 2020b ) and beagle dogs ( Zhang et al, 2020a ), the occurrence rate and severity of hemolysis are not significantly different between the treated and control groups (35% propylene glycol). Therefore, we considered that this side-effect was related to the solvent, not ET-26HCl.…”

Section: Discussionmentioning

confidence: 98%

The preclinical pharmacological study of a novel intravenous anesthetic, ET-26 hydrochloride, in aged rats

Chen

Gong

et al. 2022

PeerJ

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Background ET-26 hydrochloride (ET-26HCl) is a novel analogue of etomidate approved for clinical trials. However, all results from recent studies were accomplished in young adult animals. The objective of this study was to evaluate the efficacy and safety of ET-26HCl in aged rats. Methods Aged Sprague-Dawley rats were randomly divided into three groups (three males and three females in each group) were given dose of two-fold of median effective dose (ED50) of ET-26HCl, etomidate and propofol: the measurements of loss of the righting reflex (LORR) and cardiovascular and respiratory function after injection at the two-fold dose of the median effective dose were used for evaluation of effectiveness and safety, and the modified adrenocorticotropic hormone-stimulation experiment was used to evaluate the inhibition effect of the drugs on the synthesis of adrenal cortical hormones. Results There was no significant difference in the onset time among propofol, etomidate and ET-26HCl. The duration of propofol (850.5 ± 77.4 s) was significantly longer than that caused by etomidate (489.8 ± 77.0 s, p = 0.007) and ET-26HCl (347.3 ± 49.0 s, p = 0.0004). No significant difference was observed in the time to stand and normal activity among drugs. A total of 66.7% of rats in the ET-26HCl group were evaluated to have mild hematuria. Then, etomidate and ET-26HCl had a milder blood pressure inhibition effect than propofol. Apnea was observed in all rats administered propofol and the duration for this side effect was 45.0 ± 9.0 s. For etomidate and ET-26HCl, no apnea was observed. No other clinical signs of side-effect were observed, and no rats died. No significant difference was observed in corticosterone concentrations between ET-26HCl and solvent group. However, rats administered etomidate had lower corticosterone concentrations than those administered ET-26HCl at 15, 30, and 60 min. Conclusions Our results indicate ET-26HCl in aged rats is an effective sedative-hypnotic with stable myocardial and respiratory performance and also have mild adrenocortical suppression. Thus, these findings increase the potential for the clinical use of ET-26HCl in the elderly population.

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“…Due to a higher survival rate, a fewer corticosterone suppression, a lower inflammatory reaction, and a lesser organ injury in the rat lipopolysaccharide-induced sepsis model, ET-26HCl could possibly be safer than etomidate in critically ill patients (Wang et al, 2017b). In the preclinical single-and repeated-dose toxicity studies (Zhang et al, 2020a;Zhang et al, 2020b), ET-26HCl caused slight changes in behavior, laboratory tests findings, organ coefficient, and macroscopic and histopathological examinations. On the basis of observations, ET-26HCl could produce a certainly and safely sedative effect with a mild adrenocortical suppression, which increased the probability of ET-26HCl for clinical use.…”

Section: Introductionmentioning

confidence: 99%

Safety Pharmacology Study of ET-26 Hydrochloride, a Potential Drug for Intravenous General Anesthesia, in Rats and Beagle Dogs

et al. 2021

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Background: ET-26 hydrochloride (ET-26HCl), a class 1 new drug, was developed to reserve the advantages of etomidate with a mild adrenocortical inhibition.Purpose: this study was to evaluate the potential adverse effects on the cardiovascular system of beagle dogs and the respiratory and central nervous systems of rats.Methods: three established methods, the whole-body plethysmography for respiratory function, the prototype telemetry transmitter for cardiovascular function, and the standardized functional observational battery for central nervous system function, were accomplished with Good Laboratory Practice standards.Results: no significant difference in the tidal volume, but the respiratory rate and minute ventilation were reduced. The degree of inhibition was the most serious in the first 15 min after dosing and function fully recovered after 1 h. For male rats, the respiratory rate of male rats was reduced significantly at 15 min after injection with ET-26HCl (4 mg/kg, 28.6%, p ≤ 0.01; 8 mg/kg, 24.5%, p ≤ 0.01; 16 mg/kg, 44.5%, p ≤ 0.001), and the minute ventilation at 15 min was decreased by 20.1% (4 mg/kg, p = 0.034), 22.2% (8 mg/kg, p = 0.019), and 44.6% (16 mg/kg, p ≤ 0.001) as compared to control group. As with male rats, the respiratory rate of the female rats was reduced significantly at 15 min (4 mg/kg, 23.3%, p ≤ 0.01; 8 mg/kg, 29.2%, p ≤ 0.001; 16 mg/kg, 44.1%, p ≤ 0.001), and the minute ventilation was decreased by 25.2% (4 mg/kg, p ≤ 0.001), 23.0% (8 mg/kg, p ≤ 0.01), and 47.6% (16 mg/kg, p ≤ 0.001). Then, all the variations in cardiovascular functions were within the expected range for normal biological variation, we concluded that ET-26HCl, even at 10-fold ED50, still does not exert toxicological effects on the cardiovascular system. For male beagle dogs, the systolic blood pressure after 24 h following administration of vehicle control or 8, 12, or 16 mg/kg ET-26HCl was 137.80 ± 5.55, 131.76 ± 10.03, 139.88 ± 8.35, and 141.28 ± 8.75 mmHg, respectively. The diastolic blood pressure was 71.16 ± 4.84, 66.52 ± 8.50, 73.64 ± 8.51, and 74.24 ± 8.68 mmHg, respectively. For female beagle dogs, the systolic blood pressure after 24 h following administration of vehicle control or 8, 12, or 16 mg/kg ET-26HCl was 128.28 ± 5.22, 124.76 ± 7.29, 134.88 ± 5.56, and 135.36 ± 8.72 mmHg, respectively. The diastolic blood pressure was 67.00 ± 4.10, 62.12 ± 7.87, 69.44 ± 6.40, and 70.20 ± 8.42 mmHg, respectively. In central nervous system function experiment, all the changes observed in the functional observational battery tests, including motor activity, behavior, coordination, and sensory and motor reflex responses, and reduced body temperature, were resulted in general anesthesia effect of ET-26HCl.Conclusion: ET-26HCl exerts mild, reversible effects on respiratory, cardiovascular, and central nervous system function as verified by standard in vivo animal models.

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Non‐clinical single‐ and repeated‐dose toxicity studies of ET‐26 hydrochloride in rats

Cited by 4 publications

References 13 publications

Novel anesthetics in pediatric practice: is it time?

Novel anesthetics in pediatric practice: is it time?

The preclinical pharmacological study of a novel intravenous anesthetic, ET-26 hydrochloride, in aged rats

Safety Pharmacology Study of ET-26 Hydrochloride, a Potential Drug for Intravenous General Anesthesia, in Rats and Beagle Dogs

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